title: Novel methylation biomarker panel for the early detection of pancreatic cancer.
abstract: OBJECTIVE
  Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer.
  
  
  METHODS
  We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum.
  
  
  RESULTS
  We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%).
  
  
  CONCLUSIONS
  Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.|Research Institute, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, South Korea.
authors.forename: Joo Mi
authors.initials: JM
authors.lastname: Yi
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Guzzetta
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, Baltimore, MD, USA.
authors.forename: Vasudev J
authors.initials: VJ
authors.lastname: Bailey
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Downing
authors.affiliation: MDxHealth, Ghent, Belgium.
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Chiappinelli
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, Baltimore, MD, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Keeley
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, Baltimore, MD, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Stark
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Herrera
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wolfgang
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Emmanouil P
authors.initials: EP
authors.lastname: Pappou
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Goggins
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, Baltimore, MD, USA.|Department of Mechanic Engineering, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tza-Huei
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.|Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071097:ADAMTS1 Protein; D014408:Biomarkers, Tumor / Q000235:genetics*; D002278:Carcinoma in Situ / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands; D004247:DNA / Q000097:blood / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D055088:Early Detection of Cancer; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C077914:BNC1 protein, human; D004247:DNA; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human